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JACC: CARDIOVASCULAR INTERVENTIONS VOL. 6, NO. 12, 2013

ª 2013 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 1936-8798/$36.00

PUBLISHEDBYELSEVIERINC. http://dx.doi.org/10.1016/j.jcin.2013.06.014

Concomitant Administration of Clopidogrel With or Calcium-Channel Blockers Insights From the TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Inhibition With Prasugrel– In 38)

Oluseyi Ojeifo, MD,* Stephen D. Wiviott, MD,y Elliott M. Antman, MD,y Sabina A. Murphy, MPH,y Jacob A. Udell, MD,z Eric R. Bates, MD,x Jessica L. Mega, MD, MPH,y Marc S. Sabatine, MD, MPH,y Michelle L. O’Donoghue, MD, MPHy

Boston, Massachusetts; Toronto, Ontario, Canada; and Ann Arbor, Michigan

Objectives This study sought to evaluate the clinical relevance of potential clopidogrel –drug interactions.

Background Some studies have demonstrated that statins and calcium-channel blockers (CCBs) may attenuate the pharmacodynamic effects of clopidogrel.

Methods The TRITON–TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel–Thrombolysis in Myocardial Infarction 38) enrolled 13,608 patients with an (ACS) and planned percutaneous coronary intervention (PCI), and randomized them to clopidogrel or prasugrel. Use of a or CCB was left to the discretion of the treating physician. A multivariable Cox model with propensity score was employed to evaluate the association between statin or CCB use and clinical outcomes.

Results Of the 6,795 subjects assigned to clopidogrel, 4,794 (70.6%) were on a CYP3A4-metabolized statin, and 966 (14.2%) were on a CCB at randomization. The risk of cardiovascular (CV) death, myocardial infarction (MI), or was similar regardless of baseline use of statins (adjusted hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 0.85 to 1.22) or CCBs (adjusted HR: 1.16; 95% CI: 0.94 to 1.43) in clopidogrel-treated patients. Further, the combined use of a CCB and 80 mg daily (adjusted HR: 0.82; 95% CI: 0.37 to 1.84), or a CCB, statin, and proton pump inhibitor (adjusted HR: 1.04; 95% CI: 0.70 to 1.54) were not associated with an increased risk of CV death, MI, or stroke. The use of statins or CCBs did not modify the relative efficacy of prasugrel versus clopidogrel for the primary endpoint (p for interaction ¼ 0.43, 0.55, respectively).

Conclusions In patients with ACS undergoing PCI, the use of statins or CCBs was not associated with an increased risk of CV events in clopidogrel-treated patients. Consistent results were observed when the were administered alone, together, or in combination with proton pump inhibitors. (J Am Coll Cardiol Intv 2013;6:1275–81) ª 2013 by the American College of Cardiology Foundation

From the *Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts; yTIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts; zDivision of Cardiology, Women’s College Hospital, University of Toronto, Toronto, Ontario, Canada; and the xDepartment of Internal Medicine, University of Michigan, Ann Arbor, Michigan. Dr. Wiviott is a consultant for Angelmed, Eisai, Aegerion, Janssen Pharmaceuticals, St. Jude Medical, and Xoma; and has received research funding from Merck & Co., Eisai, AstraZeneca, and Eli Lilly and Company/Daichi Sankyo. Dr. Antman has received research funding from Eli Lilly and Company and . Ms. Murphy has received research funding from Eli Lilly and Company. Dr. Bates is on the advisory boards of Daichi Sankyo, AstraZeneca, Eli Lilly and Company, and Sanofi-aventis. Dr. Mega has received research funding from Jannsen Pharmaceuticals, HealthCare, AstraZeneca, Eli Lilly and Company, Daiichi Sankyo, Bristol-Myers Squibb, and Sanofi- aventis; and is a consultant for Boehringer Ingelheim and Janssen Pharmaceuticals. Dr. Sabatine has received research funding through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, AstraZeneca, AstraZeneca/Bristol-Myers Squibb Alliance, Critical Diagnostics, Daiichi-Sankyo, Eisai, Genzyme, GlaxoSmithKline, Intarcia, Merck, Roche Diagnostics, Sanofi-aventis, and Takeda; and is a consultant for Aegerion, Amgen, AstraZeneca/Bristol-Myers Squibb Alliance, Intarcia, Pfizer, Sanofi-aventis, and Vertex. Dr. O’Donoghue has received research funding from GlaxoSmithKline and AstraZeneca and is a consultant for Aegerion. All other authors have reported that 1276 Ojeifo et al. JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 12, 2013 Clopidogrel and Drug Interactions DECEMBER 2013:1275– 81

Statins and calcium-channel blockers (CCBs) are frequently dates of concomitant were captured on the case co-administered with clopidogrel after an acute coronary report forms at patient visits. For the current analysis, we syndrome (ACS). Because clopidogrel requires hepatic me- defined statin use as all statins that were known to be tabolism via the (CYP) system to metabolized by the CYP3A4 enzyme system, including form its active metabolite, there exists concern that certain atorvastatin, , , and . On drugs, such as statins or CCBs, that are metabolized by or the basis of prior pharmacodynamic studies (1–3),we inhibit isoenzymes along this pathway, can interfere with the also examined atorvastatin use individually in a sensitivity clinical efficacy of clopidogrel. analysis. CCB use was defined as any of the following subtypes that are metabolized by or inhibit the CYP3A4 See page 1282 isoenzyme, including diltiazem, verapamil, nifedipine, felo- dipine, , nisoldipine, isradipine, nimodipine, nicardipine, lercanidipine, nitrendipine, bepridil, lacidipine, These concerns are supported by studies that have barnidipine, and azelnidipine. demonstrated that atorvastatin (1–3) or CCBs (4–6) can All primary efficacy and key safety endpoints were adju- attenuate the pharmacodynamic effects of clopidogrel in dicated by an independent clinical events committee who vitro; however, the results from pharmacodynamic studies were unaware of the assigned treatment; however, the use of remain mixed (7) and the clinical implications of these concomitant medications including CCBs and statins was findings remain unclear. We therefore assessed whether not concealed. For the current analysis, stent was statins or CCBs interfere with the clinical efficacy of clo- defined according to the Academic Research Consortium pidogrel in a large trial population of patients with ACS (ARC) definite or probable definitions (9). undergoing percutaneous coro- Statistical analysis. Baseline characteristics are presented as Abbreviations nary intervention (PCI). Fur- medians (interquartile ranges) for continuous variables and and Acronyms ther, we assessed the relative frequencies for categorical variables. Comparisons for base- fi ACS = acute coronary ef cacy and safety of prasugrel line characteristics were made with Wilcoxon rank sum tests syndrome versus clopidogrel in those for continuous variables and chi-square tests for categorical CCB = calcium-channel subjects who were treated with variables. blocker statins or CCBs. Multivariable Cox proportional hazards model was used CI = confidence interval to examine the independent association between use of CV = cardiovascular Methods a statin and/or CCB and the risk of adverse outcomes for

HR = hazard ratio patients on clopidogrel. Using logistic regression modeling – < MI = myocardial infarction The TRITON TIMI 38 (Trial with a forward selection algorithm (p for inclusion 0.20), to Assess Improvement in Ther- propensity scores were developed to account for the clini- PCI = percutaneous coronary ’ fi intervention apeutic Outcomes by Optimiz- cian s decision to treat with a statin or CCB. The nal ing Platelet Inhibition With variables included in each propensity score and multivariable Prasugrel–Thrombolysis in Myo- models are included in the Online Appendix.Because cardial Infarction 38) study was a double-blind, phase 3 trial patients could start or stop medications during the course of that enrolled 13,608 patients with moderate-to-high-risk study, we conducted sensitivity analyses that were restricted to ACS undergoing planned PCI, and randomized them to those subjects on a concomitant of interest both at prasugrel (60-mg loading dose, 10 mg a day maintenance dose) randomization and at the end of the study. or clopidogrel (300-mg loading dose, 75 mg a day maintenance All efficacy analyses comparing prasugrel with clopidogrel dose) for a median duration of 14.5 months (8).Theprimary were conducted according to the intention-to-treat prin- endpoint of the TRITON–TIMI 38 trial was the composite of ciple. Rates of endpoints are expressed as Kaplan-Meier cardiovascular (CV) death, nonfatal myocardial infarction estimates at 450 days. All tests were 2-sided with a signifi- (MI), or nonfatal stroke. Relevant exclusions to participation cance value of p < 0.05. Analyses were performed with Stata in the trial included an increased risk of bleeding, a history version 9.2 (Stata Corp., College Station, Texas). of anemia, thrombocytopenia, or pathological intracranial findings. Results Statin or CCB use. The decision to treat with a statin or CCB was left to the discretion of the treating physician. The Of the 13,608 patients enrolled in the TRITON–TIMI names (brand name or generic), doses, and start and stop 38 trial, 9,580 (70.4%) were recorded to be taking they have no relationships relevant to the contents of this paper to disclose. The Study Group has an independent copy of the trial database and conducted the current TRITON–TIMI 38 trial was sponsored by Daiichi Sankyo and Eli Lilly and analysis. Company. The current analysis received no sources of external funding. The TIMI Manuscript received April 29, 2013; accepted June 21, 2013. JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 12, 2013 Ojeifo et al. 1277 DECEMBER 2013:1275– 81 Clopidogrel and Drug Interactions

Table 1. Baseline Characteristics Stratified by Use of a CYP3A4-Metabolized Statin or CCB

CCB at No CCB at Statin at No Statin at Randomization Randomization Randomization Randomization (n ¼ 1,972) (n ¼ 11,636) p Value (n ¼ 9,580) (n ¼ 4,028) p Value

Age 75 yrs 19.2 12.3 <0.001 12.2 16.0 <0.001 Male 70.7 74.7 <0.001 74.8 72.5 <0.001 White race 91.4 92.7 0.054 91.9 94.0 <0.001 Region <0.001 <0.001 North America 40.9 30.1 30.6 34.2 South America 2.4 4.2 4.4 2.8 Western Europe 20.8 27.0 24.7 29.6 Eastern Europe 15.2 26.0 24.7 23.7 Rest of the World 20.7 12.7 15.7 9.7 BMI, kg/m2 28.7 (25.7–32.2) 27.7 (25.1–30.9) <0.001 27.8 (25.2–31.2) 27.6 (24.9–30.8) <0.001 Current tobacco use 30.8 39.4 <0.001 38.4 37.6 0.38 Hypertension 82.4 61.2 <0.001 64.6 63.3 0.15 Hypercholesterolemia 64.6 54.2 <0.001 59.1 47.6 <0.001 Diabetes mellitus 31.5 21.7 <0.001 24.1 20.7 <0.001 Peptic ulcer disease 6.3 5.9 0.48 6.2 5.5 0.11 Carotid or vertebral arterial 4.7 2.6 <0.001 2.8 3.1 0.36 History stroke or TIA 6.2 3.4 <0.001 3.8 3.9 0.65 History of peripheral arterial disease 8.8 4.6 <0.001 5.4 4.9 0.32 Prior MI 23.9 16.9 <0.001 19.1 15.0 <0.001 Prior CABG 12.2 6.9 <0.0001 8.2 6.3 <0.001 Creatinine clearance <60 ml/min/m2 15.2 10.4 <0.001 10.3 13.2 <0.001 Index diagnosis of NSTEMI or UA 85.2 72.1 <0.001 75.2 71.2 <0.001 ACEI/ARB at randomization 68.3 54.1 <0.001 60.8 45.0 <0.001 Beta-blocker at randomization 70.7 74.5 <0.001 77.5 65.5 <0.001 Aspirin at randomization 97.3 96.6 0.12 97.6 94.6 <0.001 Randomized to prasugrel 51.0 49.9 0.36 50.0 50.3 0.70

Values are % or median (interquartile range). ACEI ¼ angiotensin-converting ; ARB ¼ angiotensin receptor blocker; BMI ¼ body mass index; CABG ¼ coronary artery bypass graft surgery; CCB ¼ calcium-channel blocker; MI ¼ myocardial infarction; NSTEMI ¼ non–ST-segment elevation myocardial infarction; PCI ¼ percutaneous coronary intervention; TIA ¼ transient ischemic attack; UA ¼ unstable . a CYP3A4-metabolized statin, and 1,972 (14.5%) were through long-term follow-up was similar for patients who recorded to be taking a CCB at the time of randomization. were (11.9%) or were not (12.4%) on a CYP3A4-metabo- The baseline characteristics for patients who were or were not lized statin (unadjusted hazard ratio [HR]: 0.94; 95% taking statins or CCBs are shown in Table 1. The frequency confidence interval [CI]: 0.81 to 1.10; p ¼ 0.43) (Fig. 1). of use of the different types of CYP3A4-metabolized statins After multivariable adjustment including the propensity to and CCBs is included in Online Tables 1 and 2. be treated with a statin, there remained no significant Patients on a CYP3A4-metabolized statin were more likely association between statin use and the risk of CV death, MI, to be younger, male, and have an index diagnosis of a non– or stroke for patients on clopidogrel (adjusted HR: 1.02; ST-segment elevation ACS compared with patients not on 95% CI: 0.85 to 1.22; p ¼ 0.83) (Table 2). Similarly, statin a statin (Table 1). Subjects treated with a statin were more use was also not associated with an increased risk of CV likely to have a history of , mellitus, death or MI (adjusted HR: 1.02; 95% CI: 0.85 to 1.23; and prior MI or coronary artery bypass graft surgery, but were p ¼ 0.84) (Table 2). less likely to have a reduced creatinine clearance (Table 1). Because patients could start or stop a statin during the Patients treated with a CCB were more likely to be older, course of follow-up, we examined those clopidogrel-treated female, and have additional risk factors including hyper- patients who were recorded to be consistently taking tension, hyperlipidemia, diabetes, prior MI, family history of a CYP3A4-metabolized statin both at randomization and at CAD, cerebrovascular disease, peripheral arterial disease, the end of the study (n ¼ 3,841, 56.5%). The consistent use and congestive failure. of statins was not associated with an increased risk of CV Statins and clinical outcomes. For patients randomized to death, MI, or stroke (adjusted HR: 0.96; 95% CI: 0.74 to clopidogrel, the Kaplan-Meier rate of the primary endpoint 1.25; p ¼ 0.78) or CV death or MI (adjusted HR: 0.95; 95% 1278 Ojeifo et al. JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 12, 2013 Clopidogrel and Drug Interactions DECEMBER 2013:1275– 81

HR: 1.16; 95% CI: 0.94 to 1.43; p ¼ 0.18) or CV death or MI (adjusted HR: 1.17; 95% CI: 0.93 to 1.45; p ¼ 0.17) (Table 2). For those clopidogrel-treated patients who were recorded to be taking a CCB both at the start and end of the study (n ¼ 582, 10.5%), the consistent use of CCBs was not associated with an increased risk of CV death, MI, or stroke (adjusted HR: 1.06; 95% CI: 0.80 to 1.40; p ¼ 0.71) or CV death or MI (adjusted HR: 1.02; 95% CI: 0.77 to 1.37; p ¼ 0.87). Patients on a CCB had a comparable reduction in CV death, MI, or stroke with prasugrel versus clopidogrel (HR: 0.87; 95% CI: 0.68 to 1.10), as compared with those patients not on a CCB (HR: 0.80; 95% CI: 0.71 to 0.90, p for interaction ¼ 0.55) (Fig. 2). Prasugrel also significantly reduced the risk of stent thrombosis for patients who were Figure 1. Risk of CV Events for Clopidogrel-Treated Patients With or (HR: 0.30; 95% CI: 0.16 to 0.58) or were not (HR: 0.53; Without a Statin 95% CI: 0.39 to 0.74) on a CCB (p for interaction ¼ 0.13). Unadjusted Kaplan-Meier curves for risk of cardiovascular (CV) death, Concomitant use of multiple CYP450-metabolized medications. myocardial infarction (MI), or stroke for clopidogrel-treated patients who were (blue line) or were not (red line) on a CYP3A4-metabolized statin at In the event that a clinical threshold effect may exist for the randomization. The risk of CV events was similar for clopidogrel-treated pharmacodynamic effects of clopidogrel, we examined CV patients regardless of background use of a statin. risk in those patients who were treated simultaneously with 2 or more medications that have been hypothesized to interfere with the conversion of clopidogrel to its active metabolite. In clopidogrel-treated patients, 694 individuals were simulta- ¼ CI: 0.72 to 1.24; p 0.70), as compared with those patients neously on a CYP3A4-metabolized statin and a CCB at not consistently on a statin. randomization. Within this group of patients on 2 CYP3A4- As a sensitivity analysis, we examined the association metabolized medications, there remained no significant between the use of atorvastatin and the risk of CV events for association between combined drug use and the risk of CV patients on clopidogrel, because some studies have only death, MI, or stroke (adjusted HR: 1.19; 95% CI: 0.93 to shown a pharmacodynamic interaction with clopidogrel for 1.51), as compared with those patients not on either a statin this particular statin type. When atorvastatin was examined or CCB. Similarly, there was not an increased risk of CV individually, its use was also not associated with an increased death, MI, or stroke for those patients simultaneously on risk of CV death or MI (HR: 1.07; 95% CI: 0.92 to 1.25; atorvastatin 80 mg daily and a CCB (adjusted HR: 0.82; 95% ¼ p 0.39) or stent thrombosis (HR: 0.99; 95% CI: 0.69 to CI: 0.37 to 1.84). ¼ 1.40; p 0.93) in clopidogrel-treated patients. Only 236 clopidogrel-treated subjects were on a combi- fi The ef cacy of prasugrel versus clopidogrel was similar for nation of a CCB, statin, and a proton pump inhibitor patients who were (HR: 0.79; 95% CI: 0.70 to 0.90) or were at randomization. Within this group of subjects, the not (HR: 0.86; 95% CI: 0.72 to 1.04) on a statin (p for concomitant use of 3 drugs that could interfere with the ¼ fi interaction 0.43) (Fig. 2). Prasugrel signi cantly reduced hepatic of clopidogrel was not associated with an the risk of stent thrombosis by 48% to 60% for patients who increased risk of CV death, MI, or stroke (adjusted HR: were (HR: 0.52; 95% CI: 0.37 to 0.74) or were not (HR: 0.40; 1.04; 95% CI: 0.70 to 1.54) when compared with patients ¼ 95% CI: 0.24 to 0.66) on a statin (p for interaction 0.39). on none of these medications. CCBs and clinical outcomes. Before multivariable adjustment, patients on a CCB had a higher risk of CV death, MI, or stroke through long-term follow-up, regardless of whether Discussion they were on clopidogrel or prasugrel. For patients randomized to clopidogrel, the rate of the primary endpoint throughout In a large population of patients with ACS, we found that the long-term follow-up was 15.7% for patients on a CCB versus use of statins, CCBs, or a combination of both these medi- 11.5% for those not a CCB (unadjusted HR: 1.38; 95% CI: cations did not appear to interfere with the clinical efficacy 1.15 to 1.65; p ¼ 0.001). However, after adjusting for baseline of clopidogrel. These findings are clinically relevant in light differences and the propensity to treat with a CCB, use of of prior pharmacodynamic studies that have shown con- a CCB was no longer associated with an increased risk of CV flicting results as to whether statins or CCBs may attenuate death, MI, or stroke in clopidogrel-treated patients (adjusted the acute antiplatelet effects of clopidogrel (1–6). Therefore, JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 12, 2013 Ojeifo et al. 1279 DECEMBER 2013:1275– 81 Clopidogrel and Drug Interactions

Table 2. Kaplan-Meier Event Rates Through Long-Term Follow-Up Stratified by the Use of a Statin or CCB at Randomization for Patients Treated With Clopidogrel

Statin CCB Adjusted HR Adjusted HR (95% CI) (95% CI) Treated Not TreatedTreated vs. Nontreated* Treated Not Treated Treated vs. Nontreated

CV death, MI, or stroke 11.9% (542/4,794) 12.4% (239/2,001) 1.02 (0.85–1.22) 15.7% (142/966) 11.5% (639/5,829) 1.16 (0.94–1.43) CV death or MI 11.0% (503/4,794) 11.7% (225/2,001) 1.02 (0.85–1.23) 14.4% (131/966) 10.7% (597/5,829) 1.17 (0.93–1.45)

Values are % (n/N). Adjusted hazard ratios (HRs) (95% confidence intervals [CI]) reflect the association between subjects treated with a CYP3A4-metabolized statin or calcium-channel blocker (CCB) use (as compared with those subjects not treated with a CYP3A4-metabolized statin or CCB) and the risk of clinical outcomes after adjusting for potential confounders and the propensity to treat with the drug. CV ¼ cardiovascular; MI ¼ myocardial infarction. this information provides important reassurance to clinicians bio-oxidative steps, whereas CYP3A4 is integral to the that these classes of drugs can be safely combined. second bio-oxidative step (11). Both clopidogrel and prasugrel are pro-drugs that require Lipophilic statins, including atorvastatin, simvastatin, and biotransformation via the CYP enzyme system to form their lovastatin, are metabolized by CYP3A4 and therefore compete active metabolites. Before undergoing hepatic metabolism, with clopidogrel for its substrate. In ex vivo experiments, when 85% of the clopidogrel pro-drug is converted to inactive clopidogrel and atorvastatin were exposed in equimolar esterases and therefore unable to undergo hepatic metabo- amounts to human microsomes containing CYP3A4, clopi- lism. By contrast, the metabolism of prasugrel appears to be dogrel metabolism was inhibited by >90% (13). Further, more efficient because it involves a single CYP-dependent studies have shown that atorvastatin may attenuate the anti- step, and the pro-drug is not shunted down a dead-end platelet effects of clopidogrel (1,2). These results were subse- pathway (10). Although several CYP contribute to quently validated by a prospective randomized trial that the 2-step metabolism of clopidogrel, it has been suggested showed an interaction between atorvastatin and a 300-mg (but that the greatest contribution is from the CYP3A4, not a 600-mg) loading dose of clopidogrel as assessed by light- CYP3A5, and CYP2C19 isoenzymes (11). Supporting transmission aggregometry (3). By contrast, several studies the concept that CYP3A4 plays a key role in the conversion have since been unable to demonstrate a definitive interaction of clopidogrel to its active metabolite, CYP3A4 enzyme between these classes of drugs (7). These discrepancies might activity has been shown to be inversely correlated to the in part be explained by marked differences in study designs, pharmacodynamic response to clopidogrel (12). Although population size, clopidogrel dosing, platelet function the relative contribution of different CYP450 isoenzymes to testing methodology, and concomitant medications (7).To the metabolism of clopidogrel remains unclear, 1 in vitro date, the clinical relevance of these findings has been study using human microsomes containing CYP3A4 and evaluated in several observational studies that have failed to CYP3A5 suggested that these 2 isoenzymes are primarily demonstrate that CYP3A4-metabolized statins interfere responsible for the conversion of clopidogrel to its active with the clinical efficacy of clopidogrel (14–19). metabolite (13). A second study demonstrated that the Because of their common requirement for CYP3A4 CYP2C19 isoenzyme contributes substantially to both metabolism, there exists similar concern that CCBs might

Figure 2. Efficacy of Prasugrel Versus Clopidogrel for Patients on a Statin or CCB

The relative efficacy of prasugrel versus clopidogrel for patients on a background of CYP3A4-metabolized statins or calcium-channel blockers (CCBs). Hazard ratios (HRs) (95% confidence interval [CI]) reflect the relative risk of CV death, MI, or stroke for patients treated with prasugrel as compared with those patients treated with clopidogrel. Abbreviations as in Figure 1. 1280 Ojeifo et al. JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 6, NO. 12, 2013 Clopidogrel and Drug Interactions DECEMBER 2013:1275– 81

interact with clopidogrel. This concern is supported by a pharmacodynamic interaction indeed exists between clo- several studies that have shown that CCBs attenuate the pidogrel and CCBs or statins, it is plausible that this antiplatelet effects of clopidogrel (4–6). However, as with interaction is too weak to translate into CV harm (26). statins, some studies have failed to observe a pharmacody- However, we still observed no signal toward increased risk namic interaction between these classes of drugs (20,21).To when multiple drugs that interfere with the CYP450 enzyme date, there exist limited data to determine whether use of system were combined. a CCB increases CV risk in clopidogrel-treated patients. In Study limitations. Limitations to the current analysis include a Danish registry of patients after MI, patients on a CCB the fact that use of statins and CCBs were not randomized, were observed to have an increased risk of CV events thereby increasing the risk of confounding by indication or regardless of whether or not they were treated with clopi- by other unassessed variables, and therefore, causality cannot dogrel, thereby suggesting the increase in risk was likely be definitively determined. However, we performed exten- explained by unidentified confounders (22). More recently, sive multivariable adjustment for baseline differences and there was no evidence of an interaction between clopidogrel included a propensity score to be treated with a statin or and CCB use in a post hoc analysis of 2,116 subjects in CCB in our models. The use of concomitant medications a randomized trial of 2 dosage regimens of clopidogrel post- was captured at randomization and may have changed PCI (23) or in 1,608 subjects after placement of a drug- because statins and CCBs could have been started or stopped eluting stent (21). during the course of the trial. Because DNA samples were In the current analysis of 13,608 subjects with ACS, we only available in a subset of the TRITON–TIMI 38 pop- did not find that CYP3A4-metabolized statins, CCBs, or ulation, our study was insufficiently powered to determine concomitant use of both medications attenuated the clinical whether an interaction might exist between CYP3A4- efficacy of clopidogrel. Moreover, the combination of metabolized medications and carriers of a reduced-function a proton pump inhibitor with 2 CYP3A4-metabolized drugs CYP2C19 allele. Although loss-of-function variants in the also did not demonstrate an increased risk of CV events. CYP3A4 gene exist, they are rare. These data represent one of the largest study populations to address the question of a possible drug–drug interaction Conclusions between these classes of drugs. Because the study population was drawn from a database, we were able to Overall, in patients with an ACS undergoing PCI, the carefully adjust for baseline differences and the propensity to clinical efficacy of clopidogrel did not appear to be signifi- treat with either a statin or CCB. Although patients on cantly modified by concomitant CCB and/or statin use. a CCB were found to be at increased risk of CV events, this Further, the use of statins and CCBs did not influence the excess in CV risk did not persist after multivariable adjust- relative efficacy or safety of prasugrel as compared with ment in clopidogrel-treated patients; thereby highlighting clopidogrel. Although only a randomized trial can defini- that CCB use was associated with a higher-risk patient tively establish the clinical implications of combining statins fi population rather than interfering with the ef cacy of clo- or CCBs with clopidogrel, the results of this study do not fi pidogrel. Further, the relative ef cacy of prasugrel versus support the need to avoid concomitant use of statins or clopidogrel was similar regardless of background use of CCBs in patients receiving clopidogrel. statins or CCBs, again suggesting that the clinical efficacy of clopidogrel was not attenuated in patients prescribed Reprint requests and correspondence: Dr. Michelle L. O’Do- CYP3A4-metabolized drugs. noghue, Cardiovascular Division, Brigham and Women’s Hospital, Therefore, despite the previously reported in vitro inter- TIMI Study Group, 350 Longwood Avenue, 1st Floor, Boston, action that was observed in some studies between clopi- Massachusetts 02115. 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